Stereotyped and compulsive behaviors are prominent, disabling, and notoriously treatment-resistant symptoms in multiple severe psychiatric disorders, including autism, Obsessive Compulsive Disorder (OCD), and schizophrenia. It is thought that these perseverative behaviors result from disruptions in multiple neurocognitive domains, including response inhibition and habit formation. However, the pathologic mechanisms leading to abnormal repetitive behaviors are still unknown. Though perseverative behaviors are associated with abnormal activity in cortico-striatal-thalamic (CSTC) circuits, it is still unclear how aberrant neural activity triggers these maladaptive actions. In addition, we have very limited insight into factors that lead to persistence of abnormal repetitive behaviors. Obtaining this knowledge is a critical step towards developing novel strategies for interrupting perseverative behaviors before they become hard-wired, or even completely preventing their onset. In this project, we will combine cutting-edge neuroscience technologies and translatable neurocognitive probes to identify molecular and circuit changes linked to onset, persistence, and successful treatment of perseverative behaviors, with a goal of identifying novel treatment strategies that cut across diagnostic boundaries. Though this project will focus on OCD since convergent functional imaging findings from OCD patients provide a strong clinical foundation for circuit-based translational studies, knowledge gained will be broadly applicable to other severe psychiatric disorders with perseverative thought patterns and actions. In previous work, we showed that repeated hyperstimulation of projections from orbitofrontal cortex (OFC) to ventromedial striatum (VMS) led to a progressive and stimulation-independent increase in perseverative grooming, a mouse behavior relevant to OCD in humans. This was accompanied by increased evoked activity at OFC-striatal synapses. Behavioral abnormalities persisted even in the absence of stimulation, suggesting that brief but repeated hyperstimulation of OFC-VMS projections is sufficient to yield long-lasting pathologic changes in circuit function. In this project, we will test the central hypothesis that plasticity changes at key CSTC circuit nodes underlie the induction of abnormal repetitive behaviors, and may serve as an avenue for treatment. In Aim 1, we will map the extended neural network associated with onset of abnormal repetitive behaviors, by determining the extent of plasticity changes using 1) in vivo physiology and 2) measurement of brain-wide levels of a neural plasticity marker, fosB. In Aim 2, we will determine optimal sites for treatment of compulsive/ stereotyped behaviors via blockade of abnormal activity in linked circuit nodes in transgenic OCD models; this will inform targeting strategies for brain-stimulation based treatments. In Aim 3, we will begin to identify molecular and environmental factors associated with persistence and relapse of perseverative behaviors, with a goal of finding new targets to prevent symptom entrenchment. The ultimate goal of these studies is to identify new treatment options for disabling perseverative and compulsive behaviors.